Postmortem studies have shown that brain amyloid plaques are present in 25-50% of cognitively normal elderly control subjects and recent Pittsburgh Compound-B (PiB) PET studies have shown similar findings in living cognitively normal elderly. PiB retention in some controls can be as high as that observed in Alzheimer's disease (AD). An overarching question from these findings is why, in the face of substantial amyloid burden, some people develop AD and others remain normal. Enriched environments and lifestyle have been reported to confer resistance to development of dementia (in humans) and to the effects of A2 (in animal models). The effects of enrichment are hypothesized to be related either to a decrease in pathological changes or a decrease in vulnerability to the effects of that pathology. However, although older individuals are often advised to enrich their environment, there is little data to know if environmental enrichment can have an impact late in life, or whether it must begin much earlier in life. Using a translational approach, this proposal will provide the foundation for a research program dedicated to understanding the role of environmental enrichment (and the timing of that enrichment) in conferring resistance to neurodegenerative processes. To date, my training has provided me with a strong background in animal models and human neuroimaging to separately explore research questions involving neurodegenerative diseases, such as AD. The present career development proposal seeks to extend my previous training and experience to give me the skills necessary to establish a research program that utilizes a more comprehensive translational approach that combines both animal and human studies directed at the same underlying questions. To that end, in this application I seek to explore the effects of enriched environments in "parallel" studies of both humans and animal models of AD. The research program proposed here will be built on behavioral approaches, including measurements of cognition and lifestyle, complimented by imaging techniques, including measures of A2 and metabolism in brain. Whenever possible, will to compare related measures between animal models and human subjects. The proposed career development plan reflects these goals and includes training in evaluation of cognition, A2, and metabolism in both humans and animals. This proposal addresses important questions regarding the impact of lifestyle activities on several factors including;amyloid deposition and glucose metabolism in humans and a mouse model of AD. Answers to these questions will help us to understand the significance of lifestyle activities (and the timing of those activities) on the risk for developing AD.

Public Health Relevance

Physically and cognitively stimulating activity can typically be safely manipulated and are almost universally available, making them good targets for interventions in aging and dementia. Further, it is important to understand when, during development and aging, these lifestyle interventions must be made in order to achieve optimal results. The studies proposed in this application seek to further elucidate the impact of these factors (and their timing) on the aging process and in particular, factors associated with AD.